The primary hypothesis of this proposal is that T cell recognition of alloantigen, costimulation and subsequent activation plays a critical role in orchestrating the alloimmune response responsible for initiation and progression of chronic allograft rejection. The corollary hypothesis is that inhibiting T cell activation by T cell costimulatory blockade or by Protein Kinase C inhibition will prevent progression of chronic organ dysfunction following transplantation. The secondary hypothesis is that calcineurin inhibitors (CNI) play an important role in promoting chronic allograft dysfunction because of their nephrotoxicity. Therefore, removing CNIs, along with provision of adequate, safe and non-toxic immunosuppression to inhibit T cell activation should prevent the progression of organ dysfunction, and improve renal function and long-term outcome. The overall goal of this proposal is to develop novel therapies for prevention and interruption of progression of chronic allograft dysfunction in children. We have formed a consortium of six large pediatric kidney transplant programs with proven track records of participation in multi-center collaborative randomized clinical trials of innovative immunosuppression protocols. We also have assembled five mechanistic core laboratories to define the biomarkers of chronic allograft dysfunction and the effects of novel therapeutic interventions. We are proposing two alternative trials: 1 Belatacept Protocol: In this protocol we will test the hypothesis that B7 blockade by belatacept will block ongoing alloimmune responses and allow conversion from CNI in pediatric renal transplant recipients leading to prevention of progression of chronic allograft dysfunction and improvement in renal function. In collaboration with BMS we now propose to initiate belatacept 6-24 months post-transplantation to withdraw CNI and prevent progression of chronic allograft dysfunction in pediatric kidney transplant recipients. Since belatacept is provided as once monthly intravenous infusions, the protocol has the added potential to improve immunosuppression adherence in adolescent transplant. 2 AEB071 Protocol: In this protocol, we will test the hypothesis that Protein Kinase C inhibition will effectively block ongoing alloimmune responses and permit CNI withdrawal in pediatric renal transplant recipients leading to prevention of progression of chronic allograft dysfunction and improvement in renal function. In collaboration with Novartis we now propose to initiate AEB071 6-24 months post-transplantation to withdraw CNI and prevent progression of chronic allograft dysfunction in pediatric kidney transplant recipients. 3 Mechanistic Studies: We will test the hypothesis that inhibition of T cell activation by belatacept or AEB071 will inhibit the effector mechanisms of chronic allograft rejection, including T cell alloreactivity, alloantibody production (B cells), as well as other mediators of the chronic inflammatory response. These effects can be detected by sensitive and specific assays, including peripheral cellular/humoral assays, and peripheral blood and intragraft molecular assays. The main goal of these studies is to understand the mechanisms of action of belatacept/AEB071 and to develop a set of surrogate biomarkers of chronic allograft dysfunction and stability in pediatric kidney transplant recipients.
